Subcutaneous Epcoritamab Plus R-DHAX/C Shows Promising Preliminary Activity in ASCT-Eligible, R/R DLBCL

Article
Pipeline Report: August 2022

Raul Cordoba, MD, PhD, discussed the efficacy and safety findings from cohort 4 of the EPCORE NHL-2 trial, the benefits observed with epcoritamab monotherapy in patients who did not proceed to transplant, and what the addition of epcoritamab to R-DHAX/C could mean for patients with relapsed/refractory DLBCL.

Raul Cordoba, MD, PhD

Raul Cordoba, MD, PhD

The addition of subcutaneous epcoritamab to R-DHAX/C (rituximab [Rituxan], dexamethasone, cytarabine, and oxaliplatin/carboplatin), followed by epcoritamab monotherapy, led to high response rates in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who were eligible for autologous stem cell transplant (ASCT), according to data from cohort 4 of the phase 1/2 EPCORE NHL-2 trial (NCT04663347) presented during the 2022 EHA Congress.1

Notably, responses were observed irrespective of whether a patient proceeded to ASCT. These findings prompted investigators to consider whether ASCT is always the best option for this subset of patients, according to Raul Cordoba, MD, PhD.

“In some patients, the duration of response was very long lasting, despite these patients not receiving ASCT,” Cordoba said. “We have to [question whether] ASCT is necessary in this group of patients.”

All efficacy-evaluable patients in cohort 4 (n = 26) achieved an overall response rate (ORR) of 88%, including a complete metabolic response (CMR) rate of 65% and a partial metabolic response (PMR) rate of 23%. Two patients had progressive disease, and 1 patient had no response assessment.

Specifically, in patients who proceeded to ASCT (n = 14), the ORR was 100%, with a CMR rate of 86% and a PMR rate of 14%. In patients who did not undergo ASCT, the ORR was 75%, with a 42% CMR rate and a 33% PMR rate.

In an interview with OncLive®, Cordoba, a hematologist, oncologist, and the coordinator of the Lymphoma Unit at the University Hospital Fundación Jiménez Díaz in Madrid, Spain, discussed the efficacy and safety findings from cohort 4 of the EPCORE NHL-2 trial, the benefits observed with epcoritamab monotherapy in patients who did not proceed to transplant, and what the addition of epcoritamab to R-DHAX/C could mean for patients with relapsed/refractory DLBCL.

OncLive®: What unmet needs in patients with relapsed/refractory DLBCL led to the investigation of adding epcoritamab to R-DHAX/C?

Cordoba: We know that relapsed/refractory DLBCL remains very difficult to treat. We can cure up to two-thirds of patients [with DLBCL], but one-third of patients cannot be cured when given frontline therapy with regimens such as R-CHOP [rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone]. It’s not easy to cure these patients that have relapsed disease. However, we have a second attempt to cure these patients when we offer second-line chemotherapy plus ASCT.

We need to improve the efficacy data of the current strategy that we are using to proceed to ASCT. One of the regimens that we commonly use in order to induce chemotherapy-sensitive responses in these patients is R-DHAX/C, which is a platinum-based regimen. We have to achieve at least a partial response in order to proceed to ASCT. We also have to increase this response, which can occur in around 40% to 50% of patients. In this [study], we tried to add a new treatment strategy of subcutaneous epcoritamab to this [R-DHAX/C] regimen in order to increase the efficacy and the rate of patients that can proceed to ASCT.

Why was epcoritamab selected as the agent to add to the R-DHAX/C regimen?

Subcutaneous epcoritamab [demonstrated] good safety and efficacy when given as monotherapy in previous trials. In the EPCORE NHL-2 trial, the aim was to explore epcoritamab in combination with other regimens. In arm 4 of this trial, we are exploring a cohort of patients that are eligible to receive high-dose therapy and proceed to ASCT.

What differentiated cohort 4 from others on the study?

One of the main inclusion criteria is that patients should be in the relapse setting. They also need to be candidates to receive high-dose chemotherapy and ASCT. That is why the patient characteristics are a bit different [compared with] the characteristics that we have seen in other trials, because patients were younger and they had received fewer lines of prior chemotherapy. We usually offer ASCT in second line and not in subsequent lines of therapy.

How well was this treatment tolerated? Were there any notable safety data to be aware of?

In arm 4 of this trial, there were no new safety findings. What we knew from subcutaneous epcoritamab as monotherapy was what we found in this combination arm. Regarding adverse effects [AEs], we saw one-third of patients suffer from cytokine release syndrome [CRS], which is a very common AE of these bispecific antibodies. [Notably], all [instances of CRS] were low grade at grade 1/2, and CRS resolution has been seen in all patients. The median time to resolution was short at 2 days [range, 1-8], and we didn’t have to discontinue therapy [in any patients due to CRS].

The safety profile is good. It’s very manageable, and we have not seen any new findings that would lead to stopping this combination.

What were the preliminary efficacy findings for epcoritamab plus R-DHAX/C in arm 4 of the trial?

We saw encouraging data; the ORR was 88%, [which compares favorably to] the [ORR of] 40% to 50% we see when we use only chemotherapy in historical cohorts. Additionally, [65%] of patients achieved a CMR. We are going to be able to proceed to ASCT in more patients and offer this curative approach to a higher percentage of patients.

It is interesting to see that [12 of 26] of patients didn’t proceed to ASCT, despite it being inclusion criteria. This was because patients didn’t want to proceed with more chemotherapy and undergo ASCT. Patients could continue single-agent subcutaneous epcoritamab [if they didn’t proceed to transplant]. We have data in this group of patients that didn’t proceed to ASCT but continued with the bispecific antibody as monotherapy. We saw that half of these patients were still on treatment, and half of these patients had to discontinue their therapy because of disease progression or AEs.

Based on these new data of patients with long-lasting responses utilizing only the bispecific antibody and not undergoing ASCT, we have to wonder if it’s necessary to proceed with these toxic regimens in this subgroup of patients.

What next steps will be taken with this research?

We need to have longer follow-up, because in these preliminary data, we have short follow-up with a median of [5.8 months (range, 1.5-11.4)]. We need to have more prolonged follow-up to see if patients have sustained CMR [regardless of whether they underwent transplant]. In those that proceeded to ASCT, [we must understand] if it’s a good strategy for cure in a second attempt in patients that had relapsed disease.

It is also interesting to see the duration of response in those patients that didn’t undergo ASCT and only received the chemotherapy plus epcoritamab [before] continuing therapy with subcutaneous epcoritamab [alone]. We are going to answer the question of whether ASCT is still necessary in this group of patients. The most important thing is to have longer follow-up for this cohort of patients.

Reference

  1. Cordoba R, Falchi L, Phillips T, et al. Preliminary phase 1/2 results of subcutaneous epcoritamab + R-DHAX/C in patients with relapsed or refractory diffuse large B-cell lymphoma eligible for autologous stem cell transplant. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract P1215.
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